Quinine
is a natural white crystalline alkaloid having antipyretic, anti-malarial with
analgesic and anti-inflammatory properties and a bitter taste. It is a stereoisomer
of quinidine. The chemical formula of quinine is C20H24N2O2

Quinine
was previously superseded by chloroquine, but is now again the drug of choice
for treatment of falciparum malaria because of the rise of chloroquine resistance.
Quinine is available with a prescription in the U.S. Quinine is also used to treat
nocturnal leg cramps and arthritis and it has also been used (with limited success)
to treat people who had been infected by prions. It was once a popular heroin
adulterant.

Mechanism
of action

The
theorized mechanism of action for quinine and related anti-malarial drugs is that
these drugs are toxic to the malaria parasite, specifically by interfering with
the parasite's ability to break down and digest hemoglobin, thus starving the
parasite and/or causing the build-up of toxic levels of partially degraded hemoglobin
in the parasite.

Sources
of quinine

Quinine
was extracted from the bark of the South American cinchona tree, isolated and
named in 1820 by French researchers Pierre Joseph Pelletier and Joseph Caventou.
The name was derived from the original Quechua (Native American) word for the
cinchona tree bark, "Quina" or "Quina-Quina", which roughly means "bark of bark"
or "holy bark". Prior to 1820, the bark was first dried, ground to a fine powder,
and then mixed into a liquid (commonly wine) before being drunk.

The
large scale use of quinine as a prophylactic started around 1850, although it
had been used in un-extracted form by Europeans since at least the early 1600s.
Quinine was first used to treat malaria in Rome in 1631. During the 1600s, malaria
was endemic to the swamps and marshes surrounding the city of Rome. Over time,
malaria was responsible for the death of several Popes, many Cardinals, and countless
common citizens of Rome. Most of the priests trained in Rome had seen malaria
victims, and were familiar with the shivering brought on by the cold phase of
the disease. In addition to its anti-malarial properties, quinine is an effective
muscle relaxant, long used by the Quechua Indians of Peru to halt shivering brought
on by cold temperatures. The Jesuit priest Agostino Salumbrino, an apothecary
by training who lived in Lima, observed the Quechua using the quinine-containing
bark of the cinchoa tree for that purpose. While its effect in treating malaria
(and hence malaria-induced shivering) was entirely unrelated to its effect in
controlling shivering from cold, it was still the correct medicine for malaria.
At the first opportunity, he sent a small quantity to Rome to test in treating
malaria. In the years that followed, cinchona bark became one of the most valuable
commodities shipped from Peru to Europe.

Cinchona
trees remain the only practical source of quinine. However, under wartime pressure,
research towards its artificial production was undertaken. A formal chemical synthesis
was accomplished in 1944 by American chemists R.B. Woodward and W.E. Doering.[1]
Since then, several more efficient total syntheses have been achieved (see review
article in Angewandte Chemie, Int. Ed., 2005, 44, p. 854 ff), but none of them
can compete in economic terms with isolation of the alkaloid from natural sources.

Dosing

Quinine
is an extremely basic compound and is therefore always presented as a salt. Various
preparations that exist include the hydrochloride, dihydrochloride, sulphate,
bisulphate, and gluconate. This makes quinine dosing very complicated, because
each of the different salts has a different weight:

quinine
base 100 mg, is equivalent to

quinine
bisulphate 169 mg, is equivalent to

quinine
dihydrochloride 122 mg, is equivalent to

quinine
hydrochloride 122 mg, is equivalent to

quinine
sulphate 121 mg, is equivalent to

quinine
gluconate 160 mg.

All
quinine salts may be given orally or intravenously (IV); quinine gluconate may
also be given intramuscularly (IM) or rectally (PR).[2][3] The main problem with the rectal
route is that the dose can be expelled before it is completely absorbed, but this
can be rectified by giving half dose again.

The
IV dose of quinine is 8 mg/kg of quinine base every eight hours; the IM dose is
12.8 mg/kg of quinine base twice daily; the PR dose is 20 mg/kg of quinine base
twice daily. Treatment should be given for seven days.

The
preparations available in the UK are quinine sulphate (200 mg or 300 mg tablets)
and quinine hydrochloride (300 mg/ml for injection). Quinine is not licensed for
IM or PR use in the UK. The adult dose in the UK is 600 mg quinine dihydrochloride
IV or 600 mg quinine sulphate orally every eight hours.

In
the U.S., quinine sulphate is available as 324 mg tablets; the adult dose is two
tablets every eight hours. There is no injectable preparation of quinine licensed
in the U.S.: quinidine is used instead.[4][5]

Side
effects

It
is usual for quinine in therapeutic doses to cause cinchonism; in rare cases,
it may even cause death (usually by pulmonary edema). The development of mild
cinchonism is not a reason for stopping or interrupting quinine therapy and the
patient should be reassured. Blood glucose levels and electrolyte concentrations
must be monitored when quinine is given by injection; the patint should also ideally
be in cardiac monitoring when the first quinine injection is given (these precautions
are often unavailable in developing countries where malaria is most a problem).

Cinchonism is
much less common when quinine is given by mouth, however, oral quinine is not
well tolerated (quinine is exceedingly bitter and many patients will vomit up
quinine tablets): other drugs such as Fansidar® (sulfadoxine with pyrimethamine)
or Malarone® (proguanil with atovaquone) are often used when oral therapy is required.
Blood glucose, electrolyte and cardiac monitoring are not necessary when quinine
is given by mouth.

Quinine
can cause paralysis if accidentally injected into a nerve.

Quinine
is extremely toxic in overdose and the advice of a poisons specialist should be
sought immediately.

Quinine
and pregnancy

In
very large doses, quinine also acts as an abortifacient; in the U.S., quinine
is classed as a Category X teratogen by the Food and Drug Administration, meaning
that it can cause birth defects (especially deafness) if taken by a woman during
pregnancy. In the UK, the recommendation is that pregnancy is not a contra-indication
to quinine therapy for falciparum malaria (which directly contradicts the US recommendation),
although it should be used with caution; the reason for this is that the risks
to the pregnancy are small and theoretical, as opposed to the very real risk of
death from falciparum malaria.

Quinine
and interactions with other diseases

Quinine
can cause haemolysis in G6PD deficiency, but again, this risk is small and the
physician should not hesitate to use quinine in patients with G6PD deficiency
when there is no alternative available. Quinine can also cause drug-induced immune
thrombocytopenic purpura (ITP).

Quinine
can cause abnormal heart rhythms and should be avoided if possible in patients
with atrial fibrillation, conduction defects or heart block.

Quinine
must not be used in patients with haemoglobinuria, myasthenia gravis or optic
neuritis, because it worsens these conditions.

Non-medical
uses of quinine

Quinine
is a flavour component of tonic water and bitter lemon. According to tradition,
the bitter taste of anti-malarial quinine tonic led British colonials in India
to mix it with gin, thus creating the gin and tonic cocktail, which is still popular
today in both India and Great Britain, and in other former British colonies.

In
the United States, the Food and Drug Administration limits tonic water quinine
to 83 ppm, which is one-half to one-quarter the concentration used in therapeutic
tonic.

In France,
quinine is an ingredient of an apritif known as Quinquina.

Because
of its relatively constant and well-known fluorescence quantum yield, quinine
is also used in photochemistry as a common fluorescence standard. Tonic water,
in normal light and UV.

In
Canada, quinine is an ingredient in the carbonated chinotto beverage called Brio.

In
the UK, quinine is an ingredient in the carbonated and caffienated beverage, Irn-Bru.